Suppression of distant pulmonary metastasis of MDA-MB 435 human breast carcinoma established in mammary fat pads of nude mice by retroviral-mediated TIMP-2 gene transfer

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Title
Suppression of distant pulmonary metastasis of MDA-MB 435 human breast carcinoma established in mammary fat pads of nude mice by retroviral-mediated TIMP-2 gene transfer
Author(s)
Y K Lee; I S So; Sang Chul Lee; Jeong-Hyung Lee; Chang Woo Lee; Hwan Mook Kim; M K Park; S T Lee; D Y Park; D Y Shin; C U Park; Y S Kim
Bibliographic Citation
Journal of Gene Medicine, vol. 7, no. 2, pp. 145-157
Publication Year
2005
Abstract
Background: Previous studies have shown that TIMP-2 overexpression is a useful therapeutic tool for inhibiting tumor growth and invasion in animals. However, it has not been reported whether genetic manipulation for TIMP-2 overexpression can induce an inhibitory effect on s0pontaneous metastasis from the primary tumor site to other organs such as lungs or lymph nodes in an animal model. Methods: The present studies describe the effects of retrovirus-mediated TIMP-2 gene transfer into human breast cancer cell lines on the in vitro invasion of the tumor cells or the in vivo growth in nude mouse. Here we also used retroviral-mediated TIMP-2 overexpression by intratumoral injection for suppression of metastasis in human breast carcinoma established in the mammary fat pad of nude mice. Results: As expected, overexpression of TIMP-2 inhibited matrix metalloprotenase (MMP) activity and invasion of the tumor cells. Also, the growth rate of tumors grafted with the breast cancer cells transduced with the retrovirus vector encoding TIMP-2 cDNA was significantly slower than the growth rate of tumors grafted with the breast cancer cells transduced with a control retrovirus vector. Furthermore, single intratumoral injection of the TIMP-2 retrovirus-producing cells into human breast tumor tissue established in mammary fat pads of nude mice showed a dramatic decrease in size and number of lung metastatic tumors. Conclusions: Retrovirus-mediated TIMP-2 gene transfer into human breast cancer cells is able to down-regulate invasion and show that tumor-derived angiogenesis is reduced. In this model, retroviral-mediated transduction of TIMP-2 cDNA into a limited population of human tumor cells inhibits tumor growth and prevents distant pulmonary metastasis. These results indicate that it may not be necessary to deliver and express these genes in every single tumor cell as long as the level of expression in a limited number of transduced cells is sufficient to prevent the excessive breakdown of the extracellular matrix.
Keyword
breast cancerfat padpulmonary metastasisretroviral vectorTIMP-2
ISSN
1099-498X
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/jgm.645
Type
Article
Appears in Collections:
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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